KARDIOLOGIA POLSKA 2019; 77 (4) 490
with both antiplatelet drugs and oral antico‑
agulants (OACs). This is related to the aging of society, concomitant coronary artery disease (CAD), peripheral artery disease (PAD), heart failure, and atrial fibrillation (AF). Additionally, The rationale behind the experts’ opinion
The need for an experts’ opinion arises directly from the rapid development of pharmacology and clinical cardiology, and from the fact that an in‑
creasing group of patients requires treatment
Correspondence to:
Prof. Adam Witkowski, MD, PhD, Department of Interventional Cardiology and Angiology, Institute of Cardiology in Warsaw, ul. Alpejska 42, 04-628 Warszawa, Poland, phone: +48 22 343 41 27, email: witkowski@hbz.pl Received: February 18, 2019.
Accepted: February 20, 2019.
Published online:
February 21, 2019.
Kardiol Pol. 2019; 77 (4): 490-508 doi:10.5603/KP.a2019.0033 Copyright by Polskie Towarzystwo Kardiologiczne, Warszawa 2019
ABSTRACT
Oral anticoagulants (OACs) are widely used for prevention of systemic thromboembolism, including the reduction of the risk of stroke in patients with atrial fibrillation (AF) and prosthetic heart valves. There is also an increasing population of patients who require not only OACs, but also double antiplatelet therapy (DAPT). A typical example is a patient with AF and stable coronary artery disease or acute coronary syndrome (ACS), treated by percutaneous coronary intervention. In recent years, with the introduction of NOACs, triple or dual therapy has become safer. Regardless of these indications for the use of NOACs, rivaroxaban at a reduced dose has proved to efficiently reduce the risk of further thrombotic events when added to DAPT in patients who have suffered an ACS. However, such therapy increases the incidence of bleeding complications.
Interesting was also the potential impact of the pleiotropic mechanism of action of non–vitamin K antagonist oral anticoagulants (NOACs) through protease‑activated receptors 1 and 2, present on the platelets and many other cells, and changing the course of arterial atherosclerosis. The COMPASS trial has shown that in the group treated with rivaroxaban combined with aspirin, the primary outcome (cardiovascular death, stroke, and myocardial infarction) occurred significantly less frequently than in the group treated only with aspirin. However, a significantly higher number of bleedings was observed. In the subgroup of patients with peripheral artery disease, a significant reduction of the incidence of amputations was shown. The outcomes of the COMPASS trial might be a breakthrough in the treatment of coronary and peripheral atherosclerosis.
KEY WORDS acute coronary syndromes, antiplatelet drugs, new oral
anticoagulants, peripheral artery disease, stable angina
E X P E R T O P I N I O N A N D P O S I T I O N P A P E R
Non–vitamin K antagonist oral anticoagulants in the treatment of coronary and peripheral atherosclerosis
Expert Consensus of the Association for Cardiovascular Interventions, Working Group on Intensive Cardiac Care and Resuscitation, and Working Group on Cardiovascular Pharmacotherapy of the Polish Cardiac Society
Adam Witkowski1, Marcin Barylski2, Krzysztof J. Filipiak3, Marek Gierlotka4, Jacek Legutko5, Maciej Lesiak6, Janina Stępińska7, Wojciech Wojakowski8 1 Department of Interventional Cardiology and Angiology, Institute of Cardiology in Warsaw, Warsaw, Poland 2 Department of Internal Medicine and Cardiac Rehabilitation, Medical University of Lodz, Łódź, Poland 3 1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
4 Department of Cardiology, Institute of Medicine, University of Opole, Opole, Poland
5 Department of Interventional Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Kraków, Poland 6 1st Department of Cardiology, Poznan University of Medical Sciences, Poznań, Poland
7 Department of Intensive Cardiac Therapy, Institute of Cardiology in Warsaw, Warsaw, Poland
8 Department of Cardiology and Structural Heart Diseases, Medical University of Silesia in Katowice, Katowice, Poland
E X P E R T O P I N I O N A N D P O S I T I O N P A P E R NOACs in coronary and peripheral atherosclerosis 491 treatment with VKA + DAPT.1,2 Furthermore, the recently published COMPASS trial (Cardio‑
vascular Outcomes for People Using Anticoag‑
ulation Strategies) documented the role of ri‑
varoxaban in the prevention of cardiovascular events in patients with stable CAD and PAD.3
In this document, we discuss the novel indica‑
tions for NOACs based on recently published tri‑
als. Also, we highlight the differences in dosing regimens dependent not only on renal function and bleeding risk but also on the indication and the presence of AF. We also believe that it is in‑
creasingly important for clinicians to be familiar with the mechanisms of action and pharmacoki‑
netics of NOACs. These drugs do not require rou‑
tine monitoring of international normalized ra‑
tio (INR), which is an unquestionable advantage.
However, in the event of an urgent surgery or a bleeding episode, monitoring the effect of NO‑
ACs is more difficult and also depends on the time elapsed from the drug ingestion. Given that 4 NO‑
ACs are now available, clinicians should famil‑
iarize themselves with the impact of renal func‑
tion on the metabolism of each of these drugs to choose the optimal treatment for their patients.
The relevance of this group of drugs is high‑
lighted by the fact that they are discussed in detail in the guidelines and experts’ opinion of the Eu‑
ropean Heart Rhythm Association, the guidelines for treatment of myocardial infarction and car‑
diac revascularization, and in the European So‑
ciety of Cardiology (ESC) clinical practice guide‑
lines on the use of antiplatelet drugs.4-7 The main indications for NOACs are listed in TABLE 1.
Additionally, the outcomes of the COMPASS trial provide a basis for using rivaroxaban (2.5 mg twice daily) combined with acetylsalicylic acid (ASA) as an effective method for the prevention of mortality, stroke, and myocardial infarction in patients with stable CAD and PAD who have si‑
nus rhythm. However, it should be remembered that bleeding risk increases with this treatment, meaning that it should be always individualized depending on the risk of ischemic and hemor‑
rhagic incidents. Effective prevention of ischemic complications is the primary objective of treat‑
ment in patients with atherosclerosis. The use of this lower “vascular” dose of rivaroxaban is the beginning of a new age of pharmacological prevention of atherosclerotic complications. In the following experts’ opinion, we will attempt to explain why we believe this statement to be true.
Molecular mechanisms of action and pharma- cokinetics and pharmacodynamics of non–vi- tamin K antagonist oral anticoagulants (NO- ACs). Differences between oral anticoagu- lants and NOACs In the 20th century, the only OAC available in Poland, and other Eastern Eu‑
ropean countries, was acenocoumarol. In 2006, warfarin was registered in Poland as the sec‑
ond VKA. From the viewpoint of therapeutic there is also a significant impact of the bleeding
risk based on validated scores on the decision on the type of antithrombotic treatment.
Combination therapy with antiplatelet drugs and OACs is used not only because of coexisting CAD and AF, but also as a secondary prevention following acute coronary syndromes (ACSs) in patients who do not require long‑term antico‑
agulation for stroke prevention. The similari‑
ties between activation of the coagulation sys‑
tem and inflammatory mediators in coronary and peripheral atherosclerosis justify the use of OACs combined with antiplatelet drugs in patients with PAD. It has been shown that de‑
spite aggressive antiplatelet treatment, the re‑
sidual risk of thrombosis persists but can be re‑
duced with anticoagulants.
Clinical observations of patients with CAD, in particular after ACS, have shown that despite dual antiplatelet therapy (DAPT), the recurrence of cardiovascular events is frequent, which in‑
dicates a need for improving secondary preven‑
tion strategies. The insight into coagulation dis‑
orders, which can persist after an acute phase of an ischemic episode, has given rise to the idea of combined antiplatelet and anticoagulation ther‑
apy. Such an approach is possible because non–
vitamin K antagonist oral anticoagulants (NO‑
ACs) are less likely than vitamin K antagonists (VKAs) to cause clinically significant bleeding.
This has made it possible to conduct randomized clinical trials to assess DAPT or single antiplate‑
let therapy combined with NOAC after ACS and in patients undergoing percutaneous coronary intervention (PCI), both with coexisting AF and without. Based on the outcomes of those trials, it can be concluded that the combined treat‑
ment (NOAC + DAPT or NOAC + single anti‑
platelet drug) after ACS reduces the incidence of recurrent ischemic cardiovascular events, although at the cost of increased risk of bleed‑
ing in long‑term follow‑up. However, there was a reduced incidence of bleeding observed with NOACs after PCI as compared with standard TABLE 1 Clinical application of non–vitamin K antagonist oral anticoagulants
Clinical application Dabigatran Apixaban Edoxaban Rivaroxaban Stroke and systemic
embolism prevention in patients with nonvalvular atrial fibrillation
+ + + +
Management/
prevention of deep vein thrombosis and pulmonary embolism
+ + + +
Prevention of ischemic events in patients with atherosclerosis of coronary and peripheral arteries
‑ ‑ ‑ +
KARDIOLOGIA POLSKA 2019; 77 (4) 492
are not relevant in this group of patients.9 Fur‑
thermore, all of the above medications have a different impact on coagulation parame‑
ters, depending on the current plasma levels of the drug. Therefore, in order to correctly inter‑
pret coagulation parameters during treatment with NOACs, the physician must know the time elapsed from the last dose of the drug, and also the time to peak and trough plasma levels of the drug. The results obtained from a blood sam‑
ple collected 3 hours after taking the drug will be significantly different from those obtained after 12 or 24 hours, or even 6 hours after the drug has been taken. TABLE 2 provides the expected rang‑
es of the peak and trough plasma levels of spe‑
cific NOACs, and of the blood coagulation pa‑
rameters impacted by those drugs.4 Further‑
more, depending on the patient’s general condi‑
tion, sometimes it is necessary to consider also the changes in the half‑life of the drug, which depend, among other, on renal function. This is particularly important for dabigatran, which is metabolized mostly in the kidneys.
In the case of NOACs, fewer interactions with food have been observed as compared with VKAs. The food ingestion does not af‑
fect the action of dabigatran and apixaban, and those 2 medications can be taken with or without food.10,11 The absorption of dabiga‑
tran depends on the acid‑alkaline balance in efficiency, there is not much difference between
the 2 medications; however, because warfarin was more often used in most Western European countries, it was tested in clinical trials on anti‑
coagulation and is listed in guidelines.
NOACs made their debut on the pharmaceu‑
tical market in the first decade of the 21st cen‑
tury. Unlike VKAs, which reduce the synthesis of coagulation factors from the prothrombin group (factors II, VII, IX, and X) and of antico‑
agulant proteins C and S, the novel drugs are highly selective towards the individual compo‑
nents of the coagulation cascade, namely, fac‑
tor Xa or thrombin (factor IIa), which are com‑
mon elements of the extrinsic and the intrinsic coagulation pathways.8 A simplified diagram of the mechanisms of action of VKAs and NOACs is provided in FIGURE 1.
NOACs do not require routine monitoring of coagulation parameters, and changes in the INR do not necessitate dose adjustments. Howev‑
er, the quantitative assessment of the action of these drugs and their anticoagulant activi‑
ty might be necessary in life‑threatening con‑
ditions, such as severe thrombotic or bleeding events, the need for urgent surgery, acute hepat‑
ic or renal failure, interaction with other drugs, or overdose.
Compared with VKAs, monitoring the action of NOACs is much more difficult. The INR assays
Direct thrombin inhibitor Intrinsic coagulation
pathway
XII XIIa
XI
IX
VIII
X
V
Vitamin K antagonist Factor Xa inhibitor
Va
II IIa
Fibrinogen Fibrin
IXa
VIII
Xa
VIIa VII
XIa
Extrinsic coagulation pathway
Tissue factor FIGURE 1 Mechanism
of action of oral anticoagulants (based on Salem et al8)
E X P E R T O P I N I O N A N D P O S I T I O N P A P E R NOACs in coronary and peripheral atherosclerosis 493 agents. This issue has been discussed in detail in the new 2018 practical guidelines of the Eu‑
ropean Hearth Rhythm Association.4
The mechanism of action of NOACs is also re‑
lated to the inhibition of protease‑activated re‑
ceptors (PARs). Inhibition of PAR1 and PAR2 im‑
pacts multiple cells other than platelets and hampers a number of processes leading to ath‑
erosclerosis. Importantly, rivaroxaban affects not only PAR1 (as do VKAs and the direct throm‑
bin inhibitor dabigatran), but also PAR2, thus re‑
ducing local inflammation, migration of leuko‑
cytes through endothelium, angiogenesis, and the volume of the atherosclerotic plaque in an‑
imal models, translating directly into anti‑in‑
flammatory and antiatherosclerotic action. How‑
ever, although the PAR2 inhibition hypothesis is based on experimental in vitro models, the anal‑
ysis of other clinical trials of PAR‑affecting drugs appears to confirm that medications devoid of impact on PA2 are less beneficial. One example of such a drug is vorapaxar, a PAR1 antagonist which reduces the risk of revascularization in pa‑
tients with PAD, while increasing bleeding risk due to the dominant PAR1 distribution on plate‑
lets.14 The pleiotropic effect of rivaroxaban seems most likely if we consider the fact that beneficial effects can be observed even for small, “vascu‑
lar” doses of the drug (2 × 2.5 mg), and the reduc‑
tion of the primary endpoint, namely, all‑cause mortality, in the COMPASS trial is characteris‑
tic for pleiotropic drugs. The mechanism of ac‑
tion of NOACs through PAR1 and PAR2 is illus‑
trated in FIGURE 2.15 the gastrointestinal tract, but drugs such as
proton pump inhibitors and H2 receptor antag‑
onists have only a minor impact on its absorp‑
tion. Thus, dabigatran can be taken concomi‑
tantly with those agents.12,13 On the other hand, taking rivaroxaban with food increases its ab‑
sorption and bioavailability by around 39%, so it is recommended to take this drug with food.
Detailed information on the absorption, bio‑
availability, and metabolism of specific NOACs is provided in TABLE 3.
Despite the fact that, compared with VKAs, NOACs have markedly fewer interactions, ad‑
verse reactions caused by concomitant use of other substances cannot be ruled out for those TABLE 2 Plasma levels of non–vitamin K antagonist oral anticoagulants (NOACs), and blood coagulation parameters in patients treated with NOACs4
Parameter Dabigatran Apixaban Edoxaban Rivaroxaban Expected peak plasma
level range, ng/ml 64–443 69–321 91–321 184–343
Expected trough plasma level range, ng/ml
31–225 34–230 31–230 12–137
PT ↑ (↑) ↑(↑) ↑↑(↑)
aPTT ↑↑(↑) (↑) ↑ ↑
ACT ↑(↑) ↑ ↑ ↑
dTT ↑↑↑↑ – – –
Abbreviations: ACT, activated clotting time; aPTT, activated partial thromboplastin time; dTT, diluted thrombin time; PT, prothrombin time
TABLE 3 Absorption and metabolism of non–vitamin K antagonist oral anticoagulants4
Properties Dabigatran Apixaban Edoxaban Rivaroxaban
Bioavailability, % 3–7 50 62 66 when taken without food;
80–100 with food
Prodrug Yes No No No
Nonrenal/renal clearance in percentages of the dose (with nonimpaired renal function), %
20/80 73/27 50/50 65/35
Binding to plasma proteins, % 35 87 55 95
Hepatic metabolism: using CYP3A4 No Yes (elimination, moderate participation of CYP3A4 ~25%
Minimal (elimination
<4%) Yes (hepatic elimination
~18%) Absorption depending on food intake No impact No impact Absorption improved
by 6%–22% Absorption improved by 39%
Absorption depending on the use of H2 receptor antagonists and proton pump inhibitors, %
–12 to –30 No impact No impact No impact
Asian patient effect, % +25 No impact No impact No impact
Half‑life, h 12–17 12 10–14 5–9 in younger patients;
11–13 in older patients
Other Dyspepsia
(5%–10%) – – 15 mg/20 mg doses –
obligatory taking with food
KARDIOLOGIA POLSKA 2019; 77 (4) 494
frequent use of NOACs than VKAs, and use dual therapy, that is, OACs combined with only 1 an‑
tiplatelet agent, to reduce the risk of hemorrhag‑
ic complications. At the same time, such an ap‑
proach seems to be safe and does not increase the risk of recurrent ischemia and mortality.4,6,7
The first randomized trial to demonstrate the benefits of a single antiplatelet drug com‑
bined with warfarin was WOEST (What is the Optimal antiplatElet and anticoagulant ther‑
apy in patients with oral anticoagulation and coronary StenTing).1 The trial assessed treat‑
ment with clopidogrel and warfarin as compared with standard triple therapy with the addition of ASA. The risk of bleeding events was reduced in the group treated only with clopidogrel and VKA compared with the standard triple thera‑
py, mainly due to lower rates of minor bleeding (major and minor bleedings, 14.0% vs 31.3%, re‑
spectively, P <0.0001; major bleedings, 3.2% vs 5.6%, P = 0.16). The rate of myocardial infarc‑
tions (3.25% vs 4.6%), stroke (1.1% vs 2.8%), re‑
peated target vessel revascularization (7.2% vs 6.7%), and stent thrombosis (1.4% vs 3.2%) did not differ significantly between the groups. To‑
tal mortality after 1 year was significantly lower in the dual therapy group (2.6% vs 0% to 6.4%, P = 0.027).1 Nevertheless, the study lacked sta‑
tistical power to allow a reliable assessment of the impact of the applied therapies on long‑term clinical outcomes.
Further studies compared strategies of stan‑
dard triple therapy (VKA + DAPT), NOAC and a single antiplatelet agent versus NOACs and Outcomes of randomized trials comparing
vitamin K antagonists and non–vitamin K antagonist oral anticoagulants in patients with atrial fibrillation undergoing percuta- neous coronary intervention Optimal com‑
bined antiplatelet and anticoagulant therapy and the length of the combined treatment in pa‑
tients with AF undergoing PCI is still extensive‑
ly studied. Initiating 1 or 2 antiplatelet agents after PCI in patients who require anticoagulant treatment increases the bleeding risk. Dual anti‑
platelet treatment can be shortened or extended, depending on the clinical and angiographic as‑
sessment of the patient, rather than the type of the stent used (drug‑eluting stent or bare metal stent). Drug‑eluting stents are associated with a lower risk of stent thrombosis in the long‑term than bare metal stents. Furthermore, recent studies suggest that short DAPT (1 month after the procedure in patients with stable angina, or 6 months after ACS) is safe for elderly patients and those with a high risk of bleeding compli‑
cations.16-19 The currently applicable treatment strategies for patients after elective PCI, pub‑
lished in the guidelines are constantly evolving according to the outcomes of the latest research.
The trend of those changes especially in patients with high bleeding risk leans towards a more
Disrupted conductivity caused by the loss of
electric conduction
between myocytes Atherosclerosis
Atrial fi brillation
Disrupted conductivity caused by the loss of
electric conduction between myocytes Cell hypertrophy
Proliferation Cardiomyopathy
Endothelial dysfunction Endothelial permeability Monocyte recruitment
Apoptosis Proteolysis Oxidative stress
Endothelial cells Smooth muscle cells
Fibroblasts Leukocytes Myocytes
Infl ammation Restenosis Angiogenesis
Cell hypertrophy Proliferation Eff ect of atrial
remodeling of the heart
Proatherogenic action
on arterial wall Cell types
Factor Xa RIVAROXABAN
Thrombin
PAR1 PAR2
Proatherogenic action
on arterial wall Eff ect of atrial remodeling of
the heart FIGURE 2 Illustration of protease‑activated receptors (PAR) 1 and 2 cellular locations,
and the potential impact of thrombin‑ or Xa‑mediated PAR activation on the blood vessel wall and the myocardium, and the resulting atherosclerotic process and atrial fibrillation (modified from Spronk et al15)
E X P E R T O P I N I O N A N D P O S I T I O N P A P E R NOACs in coronary and peripheral atherosclerosis 495 overt nonmajor bleeding, as well as of major bleeding events assessed separately, was signifi‑
cantly reduced in groups receiving dual therapy with 110 mg and 150 mg of dabigatran, as com‑
pared with standard triple therapy with VKA and DAPT. Although the lack of statistical pow‑
er of the trial did not allow for a reliable assess‑
ment of individual components of the endpoint separately, it showed that NOAC and single an‑
tiplatelet drug are noninferior to standard tri‑
ple therapy regarding the composite endpoint (death, stroke, thromboembolic events, or un‑
planned revascularization) (P = 0.005). In pa‑
tients with AF who were undergoing PCI, both doses of dabigatran used in the RE‑DUAL PCI trial, combined with a P2Y12 inhibitor, signifi‑
cantly reduced bleeding complications as com‑
pared to triple therapy with warfarin, a P2Y12 in‑
hibitor, and ASA.2 There was also equivalence in observed prevention of thromboembolic events.
Additionally, a meta‑analysis of the WOEST, PI‑
ONEER AF‑PCI, and RE‑DUAL PCI studies sug‑
gested that the probability of an increased risk of thromboembolic events during dual therapy is low compared to triple therapy.21
Two ongoing studies with NOACs (ENTRUST‑
‑AF PCI [Edoxaban Treatment Versus Vitamin K Antagonist in Patients With Atrial Fibrilla‑
tion Undergoing Percutaneous Coronary Inter‑
vention] and AUGUSTUS [A Study of Apixaban in Patients With Atrial Fibrillation, Not Caused by a Heart Valve Problem, Who Are at Risk for Thrombosis (Blood Clots) Due to Having Had a Recent Coronary Event, Such as a Heart Attack or a Procedure to Open the Vessels of the Heart]) will undoubtedly expand our knowledge and should provide answers to the questions of how long triple therapy should be used after PCI in patients with AF, and whether it should be used at all.22,23 In particular, the AUGUSTUS trial with apixaban should provide insight into whether administering dual therapy with apixaban and clopidogrel, and dual therapy with warfarin and clopidogrel, has comparable or higher efficacy than respective triple therapies, and if so, then which of the 4 studied treatment strategies is op‑
timal in terms of benefits and protection against ischemic events and the risk of bleeding compli‑
cations. The difficulties with providing the clear guidelines also arise from the fact that the stud‑
ies with both rivaroxaban and dabigatran did not have sufficient statistical power to confirm the equivalence of reduced doses of those agents in the prevention of stent thrombosis and other ischemic events.
Additionally, data supporting the combina‑
tion of NOACs with ticagrelor or prasugrel are limited. NOACs are currently not recommend‑
ed for triple therapy regimens with these more potent P2Y12 inhibitors by the latest ESC guide‑
lines. Nevertheless, the situation may be differ‑
ent in dual therapy regimens.7 In a subgroup of DAPT. The PIONEER AF‑PCI trial (Open‑Label,
Randomized, Controlled, Multicenter Study Ex‑
ploring Two Treatment Strategies of Rivaroxaban and a Dose‑Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibril‑
lation who Undergo Percutaneous Coronary In‑
tervention) assessed the safety of 3 treatment strategies after PCI with stent implantation in 2124 patients with paroxysmal, persistent, or permanent AF.20 The applied treatment regi‑
mens were as follows: 1) rivaroxaban in small doses, ie, 15 mg once daily (10 mg if creatinine clearance was 30 to 50 ml/min) plus a P2Y12 in‑
hibitor for 12 months; 2) rivaroxaban in very small doses (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months. After the completion of 1‑ or 6‑month DAPT, the patient received 15 mg once daily of rivaroxaban (10 mg if creatinine clear‑
ance was 30 to 50 ml/min) plus a small dose of ASA (75 to 100 mg/d) for the remaining part of the 12‑month treatment; 3) standard triple ther‑
apy with VKA (warfarin) once daily (target INR, 2.0–3.0) plus DAPT for 1, 6, or 12 months. The pa‑
tients treated with 1‑ or 6‑month regimens were subsequently treated with warfarin and ASA in doses as specified above for the remaining part of the 12‑month treatment.
The PIONEER AF‑PCI trial showed that both dosing regimens of rivaroxaban reduced the risk of clinically relevant bleeding complications af‑
ter 1 year of treatment, as compared with stan‑
dard triple therapy with VKA and variable dura‑
tion of DAPT (16.8% in group 1, 18.0% in group 2, and 26.7% in group; hazard ratio [HR] 1 vs 2, 0.59; 95% CI, 0.47–0.76; HR 2 vs 3, 0.63; 95% CI, 0.50–0.80). In both groups treated with rivar‑
oxaban, there was also a much lower incidence of bleeding episodes requiring medical atten‑
tion than in the standard therapy group (HR 1 vs 3, 0.61; 95% CI, 0.47–0.80; HR 2 vs 3, 0.67;
95% CI, 0.52–0.86). The rate of cardiovascular death, myocardial infarction, and stroke was comparable across the 3 groups. Nevertheless, the statistical power of the trial for the assess‑
ment of these secondary endpoints was insuf‑
ficient to draw definite conclusions. The rate of stent thrombosis was low and similar across all groups. It should also be pointed out that riva‑
roxaban 2.5 mg twice daily had not been previ‑
ously studied in the context of stroke preven‑
tion in patients with AF.20
The RE‑DUAL PCI trial (Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Un‑
dergo a PCI With Stenting) assessed the safety of 2 doses of dabigatran (110 mg or 150 mg twice daily) combined with clopidogrel or ticagrelor (dual therapy without aspirin), as compared with standard triple therapy (VKA, ASA, and clopi‑
dogrel or ticagrelor) in 2725 patients with AF who were undergoing PCI.2 The rate of the com‑
posite endpoint major bleeding and clinically
KARDIOLOGIA POLSKA 2019; 77 (4)496 TABLE 4 Summary of the outcomes of randomized trials on the use of oral anticoagulants and non–vitamin K antagonist oral anticoagulants after percutaneous coronary intervention in patients with atrial fibrillation (continued on the next page)
Trial / drug Purpose No. of
patients Selected inclusion criteria Selected exclusion criteria Endpoints Conclusions WOEST1
VKA Assessment of treatment with clopidogrel alone compared with ASA combined with clopidogrel in patients treated with oral anticoagulation after PCI
573 • Age 18–80 y
• Long‑term indication for OACs (at least 1 year after the end of study)
• Significant coronary artery disease (at least 75%
occlusion confirmed by angiography, or FFR <0.80), with an indication for PCI
• Intracranial bleeding episodes
• Cardiogenic shock
• Peptic ulcer within the previous 6 months
• Thrombocytopenia (PLT levels <50 × 109/l)
• Major bleeding within the previous 12 months (according to TIMI score)
Primary endpoint:
• Occurrence of any bleeding episode during 1‑year follow‑up Additional endpoints:
• Death
• Myocardial infarction
• Stroke
• Repeated revascularization of artery after pci
• Stent thrombosis
In patients taking OACs and undergoing PCI, the use of clopidogrel without aspirin significantly reduced hemorrhagic complications and did not increase the incidence of thrombotic events.
PIONEER AF‑PCI20 Rivaroxaban
Assessment of 3 management strategies in patients with nonvalvular AF who were undergoing PCI:
1. Rivaroxaban 15 mg or 10 mg once daily + P2Y12 inhibitor for 12 months
2. Rivaroxaban 2.5 mg twice daily + DAPT for 1, 6, or 12 months, followed by rivaroxaban 15 mg or 10 mg once daily + ASA for up to 12 months
3. Standard triple therapy with warfarin once daily (INR 2.0–3.0) + DAPT for 1, 6, or 12 months, followed by warfarin + ASA for up to 12 months
2124 • Paroxysmal, persistent, or permanent nonvalvular AF
• Current PCI with stent implantation
• History of stroke or TIA
• Clinically relevant gastrointestinal bleeding within the previous 12 months
• Creatinine clearance below 30 ml/min
• Anemia of unknown etiology with hemoglobin levels below 10 g/dl
• Other conditions known to increase bleeding risk
Primary safety endpoint:
• Occurrence of clinically relevant bleeding during 1‑year follow‑up
Secondary endpoints:
• Major bleeding, minor bleeding, bleeding episodes requiring medical consultation, analyzed separately
• Cardiovascular death, heart attack or stroke, analyzed jointly
In patients with AF who were undergoing PCI with stent implantation, treatment with rivaroxaban in small dose combined with P2Y12 inhibitor for 12 months, and rivaroxaban in very small dose combined with DAPT for 1, 6, or 12 months was associated with a lower percentage of clinically overt bleeding episodes than standard treatment with OACs combined with DAPT. The efficacy of treatment was similar across the 3 groups; nevertheless, due to the broad CIs, the trial was inconclusive in this aspect.
RE‑DUAL PCI24
Dabigatran Assessment of safety and efficacy of dual regimen (P2Y12‑inhibitor without ASA + dabigatran) compared with triple regimen (2 antiplatelet agents + warfarin) in patients with nonvalvular AF who were undergoing PCI:
1. Dabigatran 110 mg twice daily + P2Y12 inhibitor
2. Dabigatran 150 mg twice daily + P2Y12 inhibitor
3. Warfarin + P2Y12 inhibitor + ASA
<100 mg for 3 months (BMS) / 6 months (DES)
2725 • Patients with nonvalvular AF who were treated with VKAs or not before PCI, but had indications for long‑term anticoagulant therapy
• ACS treated with PCI with stent implantation, or stable coronary artery disease with ≥1 lesion effectively treated by PCI with stent implantation
• Cardiogenic shock or thrombolytic therapy of ACS
• Stroke within the previous month
• Major surgery within the previous month
• Major bleeding within the previous month
• Anemia
• Kidney failure (eCrCl
<30 ml/min), active liver disease
Primary endpoint: occurrence of a major or clinically relevant bleeding during 1‑year follow‑up
Secondary endpoint:
thromboembolic complications (heart attack, stroke or other embolism), death, or unplanned revascularization, assessed jointly
Among patients with AF who were undergoing PCI, the bleeding risk was lower in dual regimen with dabigatran and P2Y12 inhibitor than in triple regimen with warfarin, P2Y12 inhibitor, and aspirin.
The dual therapy was noninferior to triple therapy in terms of thromboembolic events risk.
EXPERT OPINION AND POSITION PAPERNOACs in coronary and peripheral atherosclerosis497
TABLE 4 Summary of the outcomes of randomized trials on the use of oral anticoagulants and non–vitamin K antagonist oral anticoagulants after percutaneous coronary intervention in patients with atrial fibrillation (continued from the previous page)
Trial / drug Purpose No. of
patients Selected inclusion criteria Selected exclusion criteria Endpoints Conclusions ENTRUST‑AF
PCI22 Edoxaban
Assessment whether anticoagulation strategy based on edoxaban reduced the risk of hemorrhagic complications of PCI compared with OACs combined with standard dual antiplatelet regimen in patients with AF who required continuous OAC. Additionally, the relative risk of ischemic events was compared between the study groups.
1. Edoxaban 60 mg (or 30 mg) once daily + P2Y12 inhibitor (clopidogrel) 2. VKA + P2Y12 inhibitor
(clopidogrel) + ASA 100 mg for 30 days
1500 • Nonvalvular AF with an indication for chronic antithrombotic therapy after a successful PCI with stent implantation
• Angiographically and clinically successful PCI
• High risk of major bleeding or a history of major hemorrhagic complications
• Ischemic stroke within the previous 2 weeks
• Uncontrolled hypertension
• Anemia (Hb <8 mg/dl)
• Kidney failure (CrCl
<15 ml/min)
Primary safety endpoint:
incidence of major and clinically overt nonmajor bleeding Primary efficacy endpoint:
cardiovascular death, stroke, thrombotic episodes,
myocardial infarction, and some stent thrombosis, assessed jointly
The outcomes have not been published. The trial is ongoing, with planned end in March 2019.
AUGUSTUS23
Apixaban Comparison of apixaban and warfarin, and the assessment of the risks and benefits of ASA in patients with AF who were treated with PCI for ACS
1. Apixaban 5 mg twice daily (2 × 2.5 mg) + P2Y12 inhibitor + ASA 2. Apixaban 5 mg twice daily (2 × 2.5 mg) + P2Y12 inhibitor 3. Warfarin + P2Y12 inhibitor + ASA 4. Warfarin + P2Y12 inhibitor*P2Y12 inhibitor for 6 months, ASA from the date of ACS to PCI/
randomization to PCI
4600 • Paroxysmal, persistent, or permanent AF requiring antithrombotic therapy
• ACS (heart attack, unstable angina) treated with PCI within the previous 14 days
• Indications for chronic anticoagulation other than AF
• Kidney failure (CrCl
<30 ml/min)
• Intracranial bleeding
• History of or planned CABG due to the presence of ACS
• Coagulopathy, active bleeding
Primary endpoint:
• Major or clinically overt non‑major bleeding within the previous 6 months Main secondary endpoint:
• All‑cause death or hospitalization
Other secondary endpoints:
• DeathHeart attack
• StrokeStent thrombosis
• Urgent revascularization
• Hospitalization
The outcomes have not been published. The trial is ongoing, with planned end in December 2018.
Abbreviations: ACS, acute coronary syndrome; AF, atrial fibrillation; ASA, acetylsalicylic acid; BMS, bare metal stent; CABG, coronary artery bypass grafting; CrCl, creatinine clearance; DAPT, dual antiplatelet therapy; DES, drug‑eluting stent; eCrCl, estimated creatine clearance; FFR, fractional flow reserve; Hb, hemoglobin; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; TIA, transient ischemic attack; PLT, platelets; VKA, vitamin K antagonist
KARDIOLOGIA POLSKA 2019; 77 (4) 498
ventricular thrombus, venous thromboembo‑
lism, etc). To reduce the bleeding risk, it is also recommended to shorten the triple therapy af‑
ter drug‑eluting stent implantation to 6 months, and in the case of a high risk of bleeding com‑
plications, to 1 month, or to use double therapy only. After early termination of triple therapy, it is recommended to continue treatment with dual therapy for up to 12 months after an ACS, with an anticoagulant (VKA or NOAC) combined with clopidogrel or ASA. After 12 months, it is recommended to switch the patient to mono‑
therapy (VKA or NOAC).7
The introduction of NOACs into clinical prac‑
tice triggered a series of studies assessing their safety and efficacy in the prevention of recurrent ischemic events in patients after ACS.
The APPRAISE II trial (Apixaban for Pre‑
vention of Acute Ischemic Events 2) assessed the outcome of treatment with apixaban, 5 mg twice daily, in patients after ACS who were re‑
ceiving standard antiplatelet therapy. A total of 7392 patients were enrolled, but the trial was terminated early due to the lack of effect of the study treatment on the incidence of car‑
diac mortality, myocardial infarction, and isch‑
emic stroke, with a significantly increased risk of hemorrhagic complications, including intra‑
cranial hemorrhages and severe fatal bleeding episodes.27
The RE‑DEEM trial (Dose Finding Study for Dabigatran Etexilate in Patients With Acute Cor‑
onary Syndrome) assessed the impact of 4 differ‑
ent doses of dabigatran (50 mg, 75 mg, 110 mg, and 150 mg twice daily), as compared with place‑
bo, on the risk of hemorrhagic complications and coagulation activity in 1861 patients after myo‑
cardial infarction (ST‑segment and non–ST‑seg‑
ment elevation myocardial infarction) who were receiving standard antiplatelet therapy.28 Dur‑
ing 6‑month follow‑up in the dabigatran group, a dose‑dependent 2‑ to 4‑fold increase of the risk of bleeding complications was observed, as well as a reduction of the procoagulation activity of plasma, with an average reduction of D‑dimer levels by 45% at 4 weeks of treatment. Howev‑
er, the trial did not have sufficient statistical power to assess the impact of different doses of dabigatran on the incidence of ischemic compli‑
cations (death, myocardial infarction, ischemic stroke) and to evaluate in detail the risk to ben‑
efit ratio for the study treatment.28
Then the ATLAS ACS 2–TIMI 51 trial (An‑
ti‑Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome‑Thrombolysis In Myocardial Infarction‑51) assessed the im‑
pact of treatment with rivaroxaban 2.5 mg twice daily and 5 mg twice daily versus placebo on the risk of ischemic and bleeding complications in 15 526 stable patients after ACS who were treated with DAPT.29 Both doses of rivaroxaban RE‑DUAL PCI, the use of ticagrelor combined
with dabigatran proved that both treatment reg‑
imens are safe and efficient.24 The outcomes of randomized trials on the use of OACs and NO‑
ACs after PCI in patients with AF are summa‑
rized in TABLE 4.
In summary, it should be noted that at the mo‑
ment, there is no definite evidence supporting the routine use of dual therapy regimens (NOAC + P2Y12 inhibitor) in patients with AF who are undergoing PCI. In patients at very high risk of recurrent ischemia, first‑line treatment should be based on 1‑ to 6‑month triple therapy regi‑
mens, as recommended by the current guide‑
lines. If the bleeding risk dominates, as an al‑
ternative to the current regimens, dual therapy initiated immediately after PCI should be con‑
sidered for patients with nonvalvular AF who require chronic anticoagulation treatment: 1) with rivaroxaban: 15 mg once daily combined with clopidogrel (10 mg with creatinine clear‑
ance of 30 to 49 ml/min); 2) with dabigatran:
150 mg twice daily or 110 mg twice daily com‑
bined with clopidogrel or ticagrelor.
Randomized trials with non–vitamin K antag- onist oral anticoagulants (NOACs) in acute coronary syndromes and their clinical impli- cations. The role of NOACs in acute coronary syndrome treatment: current guidelines of the European Society of Cardiology The es‑
sential component of the treatment after ACS, regardless of the adopted strategy (pharmacolog‑
ical treatment, PCI, and/or CABG), is 12‑month DAPT, with the combination of ASA and more potent P2Y12 inhibitors (ticagrelor, prasugrel) as the preferred regimen. Combining ASA with clopidogrel is recommended only for patients taking chronic OACs (VKAs, NOACs), with con‑
traindications to new P2Y12 inhibitors, when such drugs are not available, or the patient re‑
fuses the regimen due to economic reasons.
Despite implementation of the current guide‑
line recommendations, including myocardial re‑
vascularization, DAPT, and secondary preven‑
tion including aggressive reduction of low‑densi‑
ty lipoprotein cholesterol, patients after ACS are still exposed to high risk of recurrent cardiovas‑
cular events. This might be partially related to prolonged increased thrombin production, which is observed in patients after ACS.25 There is evi‑
dence that OACs can efficiently reduce the rate of ischemic events after ACS, and that the combina‑
tion of OACs and antiplatelet agents is more ef‑
ficient than using each of the class of drugs sep‑
arately. However, combined therapy with war‑
farin or acenocoumarol is related to increased risk of bleeding complications.26 Therefore, us‑
ing OACs combined with antiplatelet drugs is recommended only in patients after ACS who have other indications for chronic anticoagu‑
lation (AF, mechanical valve prosthesis, left
E X P E R T O P I N I O N A N D P O S I T I O N P A P E R NOACs in coronary and peripheral atherosclerosis 499 is, several years before the COMPASS trial.33 The guidelines for antiplatelet therapy in stable CAD are similar to those for PAD, recommend‑
ing a single antiplatelet agent: ASA (IA) or clop‑
idogrel (IB). Dual antiplatelet therapy is applied only to patients after PCI, and OACs are admin‑
istered only if there are additional indications.33 The COMPASS trial outcomes, published in 2017, might change the way of management of atherosclerosis, both in stable CAD and in PAD.3 The objective of the trial was to assess the safety and efficacy of rivaroxaban in mono‑
therapy, rivaroxaban in the vascular dose with aspirin, and monotherapy with aspirin in reduc‑
ing the risk of myocardial infarction, stroke, and cardiovascular death in CAD or PAD. It was a ran‑
domized, controlled, double‑blinded trial con‑
ducted until the specified number of cardiovas‑
cular events had occurred. A total of 27 395 pa‑
tients with stable atherosclerosis (CAD and/or PAD) were enrolled in the trial and randomized into 3 groups: 1) rivaroxaban, 2.5 mg twice dai‑
ly, and ASA, 100 mg; 2) rivaroxaban, 5 mg twice daily; and 3) ASA, 100 mg once daily.
Combined treatment is always associated with an increased risk of bleeding complications.
Therefore, the dose of rivaroxaban for the study arm receiving combined treatment with ASA was adjusted according to the outcomes of the ear‑
lier ATLAS ACS 2‑TIMI 51 trial, as described in the previous section.29
The COMPASS inclusion criteria provided de‑
tailed definitions of PAD and CAD. The PAD def‑
inition was as follows (one of the following cri‑
teria met):
1 History of aortofemoral bypass 2 History of limb bypass surgery
3 History of percutaneous angioplasty of ili‑
ac arteries
4 History of percutaneous angioplasty of sub‑
inguinal arteries
5 History of limb or foot amputation due to ar‑
terial disease
6 History of intermittent claudication, with at least one of the following criteria, met:
a Ankle‑brachial index <0.90
b Significant (≥50%) peripheral artery oc‑
clusion, as confirmed by angiography or Dop‑
pler ultrasound examination
7 History of revascularization of carotid arteries 8 Asymptomatic stenosis of carotid artery (≥50%), as confirmed by Doppler ultrasound examination or angiography.
CAD was defined as follows (one of the fol‑
lowing criteria):
1 Myocardial infarction over the past 20 years;
2 Multivessel CAD with current or a history of stable or unstable angina symptoms
3 Multivessel PCI 4 Multivessel CABG.
The inclusion criteria of the COMPASS tri‑
al were PAD or CAD. The CAD criterion was reduced the incidence of the primary efficacy
endpoint (cardiac death, myocardial infarction, and stroke), but increased the risk of bleeding not related to coronary artery bypass grafting and of intracranial bleeding, with no differenc‑
es in the incidence of fatal bleeding. The impact of treatment with rivaroxaban was dose depen‑
dent. The dosing regimen of 2.5 mg twice dai‑
ly significantly reduced the incidence of cardi‑
ac death (2.7% vs 4.5%, P = 0.002), as compared with placebo. This effect was not observed for the regimen of 5 mg twice daily.29
Considering the outcomes of the above stud‑
ies, the ESC guidelines for the management of ACSs without persistent ST‑segment elevation in 2015, the management of acute myocardial infarc‑
tion with ST‑segment elevation in 2017, and for myocardial revascularization in 20 185,6,30 recom‑
mended considering of adding rivaroxaban, 2.5 mg twice daily, to DAPT (grade of recommendation, IIb; level of evidence, B) only in patients: 1) with‑
out a history of stroke or transient ischemic at‑
tack; 2) treated with clopidogrel; and 3) in whom an increased risk of ischemic complications is iden‑
tified, with a low risk of bleeding complications.
Clinical implications of randomized trials with non–vitamin K antagonist oral anti- coagulants in chronic stable coronary ar- tery disease and peripheral artery disease In the ESC guidelines on PAD, antiplatelet mono‑
therapy with ASA or clopidogrel is recommend‑
ed for all symptomatic patients (IA). For asymp‑
tomatic patients with atherosclerosis of the low‑
er extremities, antiplatelet therapy is not indi‑
cated (IIIA), while in asymptomatic patients with carotid stenosis exceeding 50%, antiplate‑
let treatment with a low ASA dose should be considered (IIaC).31 Similarly, patients after pe‑
ripheral artery interventions who underwent 1‑month DAPT have indications for treatment with ASA or clopidogrel. Chronic OAC treatment is applied only in the event of concomitant in‑
dications for such therapy: in the case of AF or prosthetic heart valve implantation. Oral an‑
ticoagulants can be combined with antiplate‑
let agents in patients with a recent history of revascularization.
The purpose of antiplatelet therapy is to pre‑
vent ischemia of extremities, but also to pre‑
vent cardiovascular events, which are a com‑
mon cause of death in this population.32 Howev‑
er, the authors of the guidelines did not refer to the outcomes of the COMPASS trial, as the re‑
sults had not been published at the time. But, be‑
ing aware of the early termination of the study due to the confirmed benefits of low‑dose treat‑
ment with rivaroxaban + ASA, the authors of the guidelines took into consideration the need for further updating the guidelines.
The European guidelines for the manage‑
ment of stable CAD were published in 2013, that
KARDIOLOGIA POLSKA 2019; 77 (4) 500
that AF patients as well as patients within 1 year after ACS or stent implantation were excluded from the trial.
Other exclusion criteria in the COMPASS tri‑
al included a stroke within the previous month or any hemorrhagic or lacunar stroke, advanced heart failure: New York Heart Association func‑
tional class III or IV, significant left ventricular dysfunction (ejection fraction <30%), advanced kidney failure (estimated glomerular filtration rate <15 ml/min), and use of antiplatelet agents other than ASA.
applicable to patients aged 65 or older; for young‑
er patients, concomitant atherosclerosis in 2 or more vascular beds was required, or 2 or more additional risk factors, such as active smoking, diabetes, kidney failure (estimated glomeru‑
lar filtration rate <60 ml/min), heart failure, and nonlacunar ischemic stroke 1 month be‑
fore or earlier.
Due to those inclusion criteria, the patients who were enrolled in the trial had very advanced atherosclerosis. It should be noted that patients requiring OACs or DAPT were excluded. It means
ACS
≥12 months after ACS
Before coronary incident 12–30 months after ACS
1 year
COMPASS Rivaroxaban + ASA CHARISMA
ASA + clopidogrel
>30 months after ACS COMPASS
Rivaroxaban + ASA
TRITON ASA + prasugrel
ATLAS TIMI 51 ASA + P2Y12 + rivaroxaban CHARISMA
ASA + clopidogrel ATT Collaboration
ASA
CURE ASA + clopidogrel
PLATO ASA + ticagrelor
PEGASUS ASA + ticagrelor
CAPRIE Clopidogrel
ATT Collaboration ASA
Patient with stable CAD Patient with stable CAD
> 12 months after ACS
a
FIGURE 3 Key illustration of the experts’ opinion on the use of non–vitamin K antagonist oral anticoagulants in patients with atherosclerosis of coronary and peripheral arteries in the context of other trials on antiplatelet and anticoagulation therapies. Description: The application of optimal models of antiplatelet / anticoagulant therapy in patients with coronary artery disease (CAD) was the objective of multiple randomized clinical trials. The treatment can be divided into 3 phases: before an acute coronary syndrome (ACS) in patients with stable CAD, immediately after ACS (adopting the most common model of a 1‑year antiplatelet therapy after ACS), and follow‑up treatment, ie, more than 1 year after ACS. Given that long‑term management after ACS would not differ considerably from patient management before an ACS, the proposed figure could take the form of a circular model, where a patient who experienced an ACS many years earlier receives the same treatment as a patient under a coronary incident prevention strategy. In the figure, the “green smiley faces” indicate the outcomes of clinical trials that currently provide the strongest evidence, in an evidence‑based medicine setting, for
the preference of that model of treatment. The “red faces” indicate the trials in which the proposed model did not prove to be significantly better than the compared alternative (eg, CHARISMA trial). It should be noted that not all of the trials were randomized, prospective clinical programs (eg, ATT Collaboration); consequently, the use of acetylsalicylic acid (ASA) in monotherapy arises from an experts’ consensus based on extensive meta‑analysis of the trials, which are not marked with “faces”; some of the trials are marked as “neutral faces”: these trials provide evidence for the proposed therapy, eg, ASA + clopidogrel after ACS, or clopidogrel instead of ASA after ACS), but the outcomes of more recent trials have degraded them to less preferred management strategies than, eg, ASA + ticagrelor or ASA + prasugrel .
a An alternative only for patients without a history of stroke or transient ischemic attack, who are treated with aspirin and clopidogrel; class IIbB recommendation according to the European Society of Cardiology guidelines6
E X P E R T O P I N I O N A N D P O S I T I O N P A P E R NOACs in coronary and peripheral atherosclerosis 501 For PAD, the number of deaths was 129 out of 2492 patients (5%) in the rivaroxaban + ASA group vs 142 out of 2504 patients (6%) in the ASA group. Additionally, a significant re‑
duction in the incidence of major adverse limb events was shown, including amputations, which occurred in 32 patients (1%) treated with riva‑
roxaban + ASA vs 60 (2%) in the group treated with ASA alone (HR, 0.54; P = 0.0037).
It should be added that COMPASS was the first and thus far the only randomized tri‑
al assessing the action of NOACs in patients with chronic symptomatic atherosclerosis. Two earlier trials assessed the efficacy of warfarin in similar patient groups. The WARIS II trial (Warfarin‑Aspirin Reinfarction Study II) as‑
sessed the action of warfarin, warfarin com‑
bined with ASA, and monotherapy with ASA in the treatment of 3630 patients who had experi‑
enced a myocardial infarction.26 During 4 years of follow‑up, a significant reduction in the inci‑
dence of the composite endpoint (death, myocar‑
dial infarction, or ischemic stroke) was shown compared with monotherapy with ASA, both in patients receiving monotherapy with warfarin and in the combined therapy group. However, the use of warfarin increased the risk of major bleeding complications (P <0.001). In the WAVE trial (Warfarin Antiplatelet Vascular Evalua‑
tion Trial I), 2161 patients with PAD were ran‑
domized to groups treated with OACs combined with an antiplatelet agent, or monotherapy with an antiplatelet agent.36 During 3 years of fol‑
low‑up, in the combined therapy group, no sig‑
nificant reduction in the incidence of the com‑
posite endpoint (cardiovascular death, myocar‑
dial infarction, or stroke) or peripheral athero‑
sclerosis was shown, while an increase of the risk of life‑threatening bleeding was observed (rel‑
ative risk, 3.41; 95% CI, 1.84–6.35; P <0.001).36 In January 2018, enrollment into the VOYAG‑
ER PAD trial (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vas‑
cular Events in Subjects With Symptomatic Pe‑
ripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Ex‑
tremities) was completed; 6500 patients with PAD referred for surgical or interventional treat‑
ment, who were receiving ASA, 100 mg/d, were randomized to receive rivaroxaban, 2 × 2.5 mg, or placebo. In this study, it is acceptable to simul‑
taneously administer, for a short time follow‑
ing the intervention, P2Y12 inhibitors. The study will end after reaching the specified number of 1015 events included in the composite efficacy endpoint of cardiovascular death, myocardial in‑
farction, ischemic stroke, acute limb ischemia, or amputation. VOYAGER PAD is an international, multicenter, double‑blinded randomized trial.37 In conclusion, the outcomes of the COMPASS trial might be a breakthrough in the manage‑
ment of atherosclerosis. Combined treatment The trial was prematurely stopped due to con‑
firmation of the efficacy of rivaroxaban, 2.5 mg twice daily, combined with ASA. The group re‑
ceiving rivaroxaban, 5 mg twice daily, did not differ from ASA in terms of the occurrence of the composite endpoint, but the number of major bleeding episodes was higher in that group. The average follow‑up was 23 months.
In the group receiving rivaroxaban with ASA, the primary endpoint of cardiovascular death, stroke, and myocardial infarction occurred in 379 patients (4.1%) vs 496 (5.4%) in the ASA group (P <0.001). The relative reduction of events was 24% (HR, 0.76). Interestingly, the high‑
est reduction of major events was related to stroke, which occurred in 142 patients (1.6%) in the ASA group, and in 83 (0.9%) in the ASA + rivaroxaban group (HR, 0.58; P <0.001). In the combined treatment group, a higher inci‑
dence of major bleeding was observed, that is, in 288 patients (3.1%) vs 170 patients (1.9%), P
<0.001. The relative increase in major bleeding incidence was 70% (HR, 1.7). The number of fa‑
tal bleeding episodes and intracranial bleeding episodes did not differ significantly between the groups. The number of deaths was lower in the rivaroxaban + ASA group than in the ASA group: 313 (3.4%) vs 378 (4.1%), respectively (HR, 0.82; P = 0.01). Despite the significantly high‑
er number of bleeding complications, consid‑
ering the reduction of the composite endpoint, treatment with rivaroxaban, 2.5 mg twice dai‑
ly, combined with ASA, 100 mg once daily, pro‑
vided a clinical net benefit of 20% relative re‑
duction of cardiovascular events.
In the population of the COMPASS trial, 90.5% to 90.8% of patients in each group had CAD, while PAD was present in 27.1% to 27.4%
of the population. Peripheral artery disease was often accompanied by CAD. Aside from the out‑
comes for the entire COMPASS population, the trial outcomes were also assessed separate‑
ly in the stable CAD population and the periph‑
eral or carotid atherosclerosis group.34,35 The out‑
comes of these cohorts were consistent with the outcomes of the entire COMPASS trial. There are some aspects warranting closer attention in the assessed populations. The most common hemorrhagic complication was gastrointestinal bleeding. The trial also assessed the suitability of proton pump inhibitors for reducing the in‑
cidence of gastrointestinal bleeding, using pan‑
toprazole as the study drug. This part of the tri‑
al has not yet been published but may be useful for interpreting the outcomes.
Interestingly, a significant reduction of deaths was observed in patients with CAD treated with rivaroxaban and ASA, as compared to monother‑
apy with ASA: 262 (3%) of 8313 vs 339 (4%) of 8261, respectively (HR, 0.77; P = 0.0012), which was not observed in the PAD group. The differ‑
ence may be caused by the size of the population.
